The present invention relates to an IgE antibody production inhibitor and an autoimmune disease suppressant which are characterized by comprising a heterocyclic amide compound having a specific structure or a pharmaceutically acceptable salt thereof as an active ingredient.
The incidence of allergic diseases such as bronchial asthma, allergic rhinitis, allergic dermatitis, etc. has been increasing remarkably in recent years and is a serious social concern today. These allergic diseases are classified as Type I allergic reaction and the mechanism of pathogenesis of these diseases is suspected to be as follows.
Namely, in the first phase, the invasion of an antigen into the body results in interactions of macrophages, T cells, B cells, etc. causing production of an IgE antibody which is closely involved in Type I allergic reaction and the body is sensitized as this IgE antibody is bound to the receptors on tissue mast cells or blood basophils. In the second phase that ensues, the antigen reinvading the body attaches to the IgE antibody bound to the receptors and the resulting antigen-antibody reaction triggers a degranulation causing an extracellular release of various mediators such as histamine, SRS-A, etc. Further, in the third phase, the released mediators induce various allergic reactions owing to their smooth muscle-contacting action, vascular permeability-enhancing action, secretion-stimulating action and the like.
Many of the therapeutic agents and prophylactic agents for allergic diseases which have been developed and put on the market are drugs acting on the above-mentioned second phase or third phase. Since the basic cause of allergic diseases is the production of IgE antibodies in the body, any drug which could inhibit or suppress the production of IgE antibodies should be expected to have a remarkable efficacy for radical therapy in light of the above mechanism of pathogenesis.
Furthermore, in many cases, autoimmune diseases such as systemic lupus erythematosus, Hashimoto""s thyroiditis, myasthenia gravis, rheumatoid arthritis, Guillain-Barrxc3xa9 syndrome, glomerulonephritis, systemic erythematosus, etc. accompany an abnormal regulation of cellular immunity and humoral immunity and are associated with an abnormality or enhancement of the effector function of T cells, B cells and macrophages which is directed to autoantigens in the blood. The activation of such cellular components against autoantigens is considered to be related to the derangement of the feedback system relevant to autogenous resistance.
An autoimmune disease produces symptoms in one or more specific sites of the various organs of the body but is characterized in that such symptoms have much in common in the multiple sites. Moreover, there is a characteristic tendency that these symptoms are invariably chronic, subside unaccountably at times or flare up spontaneously, and are even associated with symptoms in other organs in the manner of a chain reaction.
It is generally acknowledged that such autoimmune diseases cause the appearance of autoantibodies in the blood, inappropriate Class II antigen expression, macrophage activation, and T-cell infiltration into target organs, and the like. However, the trigger mechanism involved in the activation of autoimmune diseases has not been made clear, nor has the mechanism of progression of autoimmune diseases been elucidated. Therefore, both prophylactic and therapeutic methods are still in quite unsatisfactory state today.
For suppressing of autoimmune diseases, various therapeutic methods inclusive of administration of drugs such as gold salts, methotrexate, antimalarials, glucocorticoids (e.g. methylprednisolone), etc.; plasmapheresis; resistance induction, etc. have been attempted but in efficacy as well as in terms of side effects, none have proved satisfactory enough.
There is an urgent need, therefore, for the development of drugs which could suppress autoimmune diseases with little risk for side effects.
In the above state of the art, the present invention has an object to provide a pharmaceutically useful IgE antibody production inhibitor comprising a substance having IgE antibody production inhibitory action as an active ingredient. A further object of the invention, in the above state of the art, is to create an entirely new autoimmune disease suppressant.
The first aspect of the present invention is an IgE antibody production inhibitor comprising a heterocyclic amide compound of the following general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient; 
wherein R represents a hydrogen atom, alkyl, xe2x80x94CHO, xe2x80x94COOH, xe2x80x94CONH2, xe2x80x94COR1, xe2x80x94COOR1, xe2x80x94CONHOR1, xe2x80x94CONHR1, CONR1R1xe2x80x2, xe2x80x94CONHSO2R1, xe2x80x94COSR1, xe2x80x94COCOR2, xe2x80x94COCOOR2, xe2x80x94CONHCOOR2, xe2x80x94COCONR3R4, xe2x80x94CSXR1, xe2x80x94SO2WR1, xe2x80x94SO2NR1R1xe2x80x2, or xe2x80x94SO2E;
R1 and R1xe2x80x2may be the same or different and each represents alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycle or heterocyclic alkyl;
R2, R3 and R4 may be the same or different and each represents a hydrogen atom, alkyl or arylalkyl, or R3 and R4 of xe2x80x94NR3R4 may be combined each other to form a heterocycle;
X represents a single bond, an oxygen atom, a sulfur atom, or xe2x80x94NHxe2x80x94;
W represents a single bond, xe2x80x94NHxe2x80x94, xe2x80x94NHCOxe2x80x94, xe2x80x94NHCOOxe2x80x94 or xe2x80x94NHCONHxe2x80x94;
E represents hydroxyl group or amino;
R5, R6 and R7 may be the same or different and each represents a hydrogen atom or alkyl, or one of R5, R6 and R7 represents aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl or heteroarylalkenyl, with each of the remaining two representing a hydrogen atom;
M represents a carbon atom or a nitrogen atom and when M represents a nitrogen atom, R6 does not exist;
Y represents cycloalkyl, aryl or heteroaryl;
Z represents a hydrogen atom, xe2x80x94CF2R8, xe2x80x94CF2CONR9R10, xe2x80x94CF2COOR9, xe2x80x94COOR9, xe2x80x94CONR9R10, a group of the following formula (i), a group of the following formula (ii), or a group of the following formula (iii);
R8 represents a hydrogen atom, halogen, alkyl, perfluoroalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, hydroxyalkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl or heteroarylalkenyl; R9 and R10 may be the same or different and each represents a hydrogen atom, alkyl, alkenyl, cycloalkyl, cycloalkylalkyl, heterocyclic alkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl or heteroarylalkenyl, or R9 and R10 of xe2x80x94NR9R10 may be combined each other to form a heterocycle; 
xe2x80x83wherein
a, b, c and d respectively represents a carbon atom or one of a, b, c and d represents a nitrogen atom with each of the remaining three representing a carbon atom;
R11, R12, R13 and R14 may be the same or different and each represents a hydrogen atom, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halogen, trifluoromethyl, cyano, nitro, xe2x80x94N17R17xe2x80x2, xe2x80x94NHSO2R17, xe2x80x94OR17, xe2x80x94COOR17, xe2x80x94CONHSO2R17 or xe2x80x94CONR17R17xe2x80x2; provided that when one of a, b, c and d represents a nitrogen atom, R11, R12, R13 or R14 combined to the nitrogen atom mentioned for a, b, c or d does not exist;
R15 and R16 may be the same or different and each represents a hydrogen atom, alkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, halogen, trifluoromethyl, cyano, nitro, xe2x80x94NR17R17xe2x80x2, xe2x80x94NHSO2R17, xe2x80x94OR17, xe2x80x94COOR17, xe2x80x94CONHSO2R17 or xe2x80x94CONR17R17xe2x80x2;
R17 and R17xe2x80x2 maybe the same or different and each represents a hydrogen atom, alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl or trifluoromethyl, or R17 and R17xe2x80x2 of xe2x80x94NR17R17xe2x80x2 may be combined each other to form a heterocycle;
A represents an oxygen atom, a sulfur atom or xe2x80x94NR18xe2x80x94; R18 represents a hydrogen atom, alkyl, cycloalkyl or cycloalkylalkyl;
n represents 0 or 1;
said alkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, arylalkenyl, heteroaryl, heteroarylalkyl, heteroarylalkenyl, heterocycle and heterocyclic alkyl may be substituted by one or more substituents respectively.
In the preferred embodiment of the first aspect of the present invention, said IgE antibody production inhibitor is a prophylactic agent for bronchial asthma, a prophylactic agent for allergic rhinitis, a prophylactic agent for allergic dermatitis, a therapeutic agent for bronchial asthma, a therapeutic agent for allergic rhinitis, or a therapeutic agent for allergic dermatitis.
The second aspect of the present invention is an autoimmune disease suppressant comprising a heterocyclic amide compound of the above general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.
In the preferred embodiment of the second aspect of the present invention, said autoimmune disease suppressant is a prophylactic agent for systemic lupus erythematosus, a prophylactic agent for Hashimoto""s thyroiditis, a prophylactic agent for myasthenia gravis, a prophylactic agent for rheumatoid arthritis, a prophylactic agent for Guillain-Barrxc3xa9 syndrome, a prophylactic agent for glomerulonephritis, a prophylactic agent for systemic erythematosus, a therapeutic agent for systemic lupus erythematosus, a therapeutic agent for Hashimoto""s thyroiditis, a therapeutic agent for myasthenia gravis, a therapeutic agent for rheumatoid arthritis, a therapeutic agent for Guillain-Barrxc3xa9 syndrome, a therapeutic agent for glomerulonephritis or a therapeutic agent for systemic erythematosus.